Single‐Nucleus Transcriptomics Reveals Microglial State Transitions and Astrocytic Trajectory Divergence During Glial Remodeling Induced by Intracortical Electrode Implantation

The foreign body response to intracortical electrodes, characterized by chronic neuroinflammation and glial scar formation, remains a primary cause of long-term functional failure. However, neurons and glial cells' heterogeneity and intercellular signaling mechanisms following electrode implantation remain poorly resolved, which is responsible for direct dysfunction. Here, we applied single-nucleus RNA sequencing (snRNA-seq) to profile the peri-implant microenvironment in rat motor cortex tissue at 3, 25, and 50 days post-electrode implantation. Integrated bioinformatic analyses, including clustering, pseudotemporal trajectory reconstruction, and cell-cell communication inference, revealed a coordinated cellular response. We identified a pathologic microglial subpopulation (marked by Gpnmb, SPP1, and CD63) and a scar-associated astrocytic subtype (characterized by Mctp1 and Lrrc7) that progressively dominate the peri-implant niche. Crucially, we reveal that neurons orchestrate these processes via CX3CL1-CX3CR1 signaling, modulating microglial polarization and PTN-ALK/Ptpprz1 interaction, promoting astrogliosis and scar formation. These findings define the dynamic neuron-glia signaling landscape surrounding chronically implanted electrodes and provide mechanistic insight into how modulating cell-cell communication may improve the long-term biocompatibility of neural interfaces.